INTRAPERITONEAL INJECTION OF TETRACYCLINES PROTECTS MICE FROM LETHAL ENDOTOXEMIA DOWN-REGULATING INDUCIBLE NITRIC-OXIDE SYNTHASE IN VARIOUSORGANS AND CYTOKINE AND NITRATE SECRETION IN BLOOD

We have tested whether tetracyclines (TETs) are able to protect mice f rom lipopolysaccharide (LPS)-induced shock, a cytokine-mediated inflam matory reaction. Mice, injected with a single dose of tetracycline bas e (TETb; 1.5, 10, and 20 mg/kg of body weight) or doxycycline (DOXY; 1 .5 mg/kg), were significantly protected from a lethal intraperitoneal injection of LPS (500 mu g per mouse), TETs acted in early events trig gered in response to LPS; in fact, they were no longer significantly p rotective if injected more than 1 h after the injection of endotoxin. LPS-treated mice protected by TETs showed a significant inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin-l alpha (IL-1 alp ha), and nitrate secretion in the blood, events that were directly rel ated with the survival. In mice treated with TETs a significant decrea se of inducible nitric oxide synthase (iNOS) activity was observed in spleen and peritoneal cells compared with that detected in mice treate d with LPS alone. Furthermore, TETs were found to inhibit NO synthesis by peritoneal macrophages stimulated in vitro with LPS. On the contra ry, TETs were unable to decrease the ability of the macrophages to syn thesize IL-1 alpha and TNF-alpha in vitro, These results indicate that TETs are not able to Bet directly on the synthesis of these cytokines , but they may modulate other pathways that could in turn be responsib le for the inhibition of IL-1 alpha, and TNF-alpha synthesis. Altogeth er, these results indicate that TETs are advantageous candidates for t he prophylaxis and treatment of septic shock in mice, having both anti microbial activity and the ability to inhibit endogenous TNF-alpha, IL -1 alpha, and iNOS, hence, exerting, potent anti-inflammatory effects.